We have recently discovered a new drug that we think may be useful in breast cancer chemotherapy. This drug is called SL0101 and was discovered by screening botanical extracts for their ability to inhibit the kinase activity of Rsk2. Out of 1,500 different plant extracts that we screened, only one was identified that specifically inhibits Rsk2 activity. The active ingredient present in this extract has been purified, and we will be able to use the purified compound for these studies.

We became interested in the kinase Rsk2 because we found that it could substantially enhance the activity of the estrogen receptor. Increased activity of the estrogen receptor is known to be important in breast cancer. Interestingly, in preliminary experiments we have observed that Rsk2 is overexpressed in a number of human breast cancer tumors compared to normal breast tissue. Malignant transformation and progression in human cancers are frequently associated with overabundance of proteins that are involved in normal cellular processes. Therefore, taken together, our studies support our hypothesis that Rsk2 is important in breast neoplasia.

Rsk2 activity is regulated by a signaling system called the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway regulates growth, and there is a substantial amount of evidence suggesting that this pathway may be important in the development and progression of breast cancer. To date, drug discovery efforts have focused on identifying inhibitors that target either MAPK or one of the kinases that regulate its activity. The importance of Rsk2 in growth and breast cancer has not been well characterized because there have been no specific inhibitors for Rsk2 activity. However, now that we have discovered an inhibitor, we are in a unique position to understand the importance of Rsk2 in breast cancer. We have determined in tissue culture that our inhibitor, SL0101, preferentially inhibits the growth of cancer cells compared to normal cells. These results are very exciting and suggest that it might be possible to preferentially inhibit the growth of breast cancer cells compared to normal breast cells. MAPK has a wide variety of functions, and clinical use of MAPK inhibitors may therefore result in a number of unwanted side effects. It is likely that Rsk2 inhibitors will have fewer side effects in the clinic than MAPK inhibitors.

In this proposal, we would like to address the following questions. (1) Can the inhibitor SL0101 preferentially inhibit the growth of breast cancer cell lines compared to normal breast cell lines? (2) Does overexpression of Rsk2 increase the growth of breast cells? (3) Can overexpression of Rsk2 initiate breast cancer in a transgenic mouse? Our studies will be done in both tissue culture and animal models. These studies will serve as the initial step in discovering the potential clinical usefulness of SL0101 and thus may serve as the basis for future patient trials. We will also determine whether Rsk2 is a valid drug target for breast cancer and further our understanding of the function that Rsk2 plays in breast neoplasia. The results of these studies may also validate Rsk2 as a useful diagnostic marker that will be used to determine patient treatment.